Nam S, Smith D M, Dou Q P
Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute and Interdisciplinary Oncology Program and Department of Biochemistry and Molecular Biology, University of South Florida College of Medicine, Tampa, Florida 33612, USA.
J Biol Chem. 2001 Apr 20;276(16):13322-30. doi: 10.1074/jbc.M004209200. Epub 2001 Jan 26.
It has been discovered that proteasome inhibitors are able to induce tumor growth arrest or cell death and that tea consumption is correlated with cancer prevention. Here, we show that ester bond-containing tea polyphenols, such as (-)-epigallocatechin-3-gallate (EGCG), potently and specifically inhibit the chymotrypsin-like activity of the proteasome in vitro (IC(50) = 86-194 nm) and in vivo (1-10 microm) at the concentrations found in the serum of green tea drinkers. Atomic orbital energy analyses and high performance liquid chromatography suggest that the carbon of the polyphenol ester bond is essential for targeting, thereby inhibiting the proteasome in cancer cells. This inhibition of the proteasome by EGCG in several tumor and transformed cell lines results in the accumulation of two natural proteasome substrates, p27(Kip1) and IkappaB-alpha, an inhibitor of transcription factor NF-kappaB, followed by growth arrest in the G(1) phase of the cell cycle. Furthermore, compared with their simian virus-transformed counterpart, the parental normal human fibroblasts were much more resistant to EGCG-induced p27(Kip1) protein accumulation and G(1) arrest. Our study suggests that the proteasome is a cancer-related molecular target of tea polyphenols and that inhibition of the proteasome activity by ester bond-containing polyphenols may contribute to the cancer-preventative effect of tea.
已发现蛋白酶体抑制剂能够诱导肿瘤生长停滞或细胞死亡，且饮茶与癌症预防相关。在此，我们表明含酯键的茶多酚，如（-）-表没食子儿茶素-3-没食子酸酯（EGCG），在体外（IC50 = 86 - 194纳米）和体内（1 - 10微摩尔）能有效且特异性地抑制蛋白酶体的胰凝乳蛋白酶样活性，该浓度在绿茶饮用者的血清中可检测到。原子轨道能量分析和高效液相色谱表明，多酚酯键的碳对于靶向作用至关重要，从而抑制癌细胞中的蛋白酶体。EGCG在多种肿瘤和转化细胞系中对蛋白酶体的这种抑制作用导致两种天然蛋白酶体底物p27（Kip1）和IkappaB-α（转录因子NF-kappaB的抑制剂）积累，随后细胞周期在G1期生长停滞。此外，与猿猴病毒转化的对应物相比，亲代正常人成纤维细胞对EGCG诱导的p27（Kip1）蛋白积累和G1期停滞更具抗性。我们的研究表明蛋白酶体是茶多酚的一个与癌症相关的分子靶点，含酯键的多酚对蛋白酶体活性的抑制可能有助于茶的防癌效果。
